Haematological effects in mice of the antitumour agents xanthenone-4-acetic acid, 5,6-methyl-xanthenone-4-acetic acid and flavone acetic acid

Abstract

Treatment of C57Bl/6 x DBA/2 mice with the maximal tolerated dose of flavone-8-acetic acid (FAA, 1300 mumol/kg), xanthenone-4-acetic acid (XAA, 1090 mumol/kg), or its dose-potent derivative 5,6-dimethyl-xanthenone-4-acetic acid (5,6-MeXAA, 100 mumol/kg) resulted within 24 h in a dramatic reduction in the number of circulating lymphocytes, an elevation in haemoglobin concentrations and a reduction in platelet numbers. Neutrophil counts either remained unchanged or were slightly elevated. All three compounds caused a marked loss of cells in the thymus. Examination of histological sections of thymus at 48 h following treatment with XAA revealed a selective depletion of cortical thymocytes and no effects on the epithelium or other thymic structures. A transient decrease in cell numbers was seen in the spleen and femoral bone marrow, with recovery to normal levels occurring within 3 days. The number of haemopoietic stem cells, colony-forming units in culture (CFU-c), in the femoral bone marrow increased after drug administration despite the occurrence of a decrease in the overall number of cells in the femur. In contrast to the increase in CFU-c numbers seen in vivo, 2 h exposure of bone-marrow cells to FAA, XAA or 5,6-MeXAA in vitro resulted in a decrease in the surviving fraction of CFU-c. The results are consistent with the hypothesis that the in vivo haematological effects of these compounds are indirect, perhaps being mediated through the induction of cytokines, and contrast with the haematological effects of conventional antitumour agents. The biochemical and haematological effects are unlikely to be the cause of the acute toxicity observed for these compounds.